The aim is to understand the regulation of gene expression, particularly in aging and in age-related dementias. Recent evidence from Drosophila and mammalian systems opens the possibility that cGMP may play a role in regulation of gene expression during reaction of the cell to environmental stresses due to heat shock and certain chemicals. Further, the control of cGMP content may be abnormal in individuals with Down syndrome and, by inference from family clustering of cases, in individuals with senile dementia of the Alzheimer type. The heat shock response in Drosphila melanogaster will be used as a model system for investigating the role of cGMP in regulation of gene expression. Molecular aspects of the heat shock response will be thoroughly analyzed by immunocytochemical procedures for identifying nuclear binding sites for cGMP, by purification and characterization of gGMP binding proteins using established biochemical and biophysical techniques, and by analysis of cellular functions which may be altered by heat shock. Findings from such studies in Drosophila will be applied to studies of cultures of fibroblasts from individuals with down syndrome and senile dementia of the Alzheimer type in order to ascertain if disordered gene expression secondary to inappropriate synthesis of cGMP can be related to abnormal phenotypes in these genetic diseases.